Based on integrative computational hybrid approaches that combined statistical coupling analysis (SCA), molecular dynamics (MD), and normal mode analysis (NMA), evolutionarily coupled residues involved in functionally relevant motion in the adenylate kinase protein family were identified. The hybrids identified four top-ranking site pairs that belong to a conserved hydrogen bond network that is involved in the enzyme's flexibility. A second group of top-ranking site pairs was identified in critical regions for functional dynamics, such as those related to enzymatic turnover. The high consistency of the results obtained by SCA with NMA (SCA.NMA) and by SCA.MD hybrid analyses suggests that suitable replacement of the matrix of cross-correlation analysis of atomic fluctuations (derived by using NMA) with those based on MD contributes to the identification of such sites by means of a fast computational calculation. The analysis presented here strongly supports the hypothesis that evolutionary forces, such as coevolution at the sequence level, have promoted functional dynamic properties of the adenylate kinase protein family. Finally, these hybrid approaches can be used to identify, at the residue level, protein motion coordination patterns not previously observed, such as in hinge regions. Proteins 2011. © 2011 Wiley-Liss, Inc.